Alopecia is a common and distressing side effect of many chemotherapeutic agents. In addition, alopecia also occurs as a side effect of radiotherapy. As patients embark on new therapies, hair loss can induce a negative body image, alter interpersonal relationships, and often cause patients to reject potentially curative therapy.
Several preventive methods have been proposed. Those methods include scalp tourniquet, scalp hypothermia, or a combination of both, the rationale of which is to reduce the blood circulation during chemotherapy or radiotherapy. However, none of those methods has been shown to have a definitive protective effect, although undesirable effects, such as headaches, may arise.
More recently, Jiminez et al. (WO 93/00079), Lishko et al. (U.S. Pat. No. 5,753,263), and Davis et al. (WO 99/15500) have disclosed methods for preventing and treating chemotherapy- and radiotherapy-induced alopecia. However, the active agents disclosed in those applications and patent are structurally distinct from the compounds of the present invention.
In spite of the research that has been done in the past, and further in view of the limited success of currently available chemotherapy-induced alopecia treatments, there is a long-felt yet unmet need in the art for an improved treatment for alopecia induced by chemotherapy and radiotherapy.
Accordingly, it is an object of the present invention to provide a new method for the treatment of alopecia induced by chemotherapy and radiotherapy.
The present invention provides a method for preventing or treating alopecia induced by chemotherapy or radiotherapy which comprises administering to a mammalian specie in need thereof a therapeutically effective amount of a compound of formulas I or II 
or enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. As used in formulas I and II, and throughout the specification, the symbols have the following meanings:
R is R6, COR7, CONH2, CONR6R7, COOR6 or SO2R6;
R6 is alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
R7 is H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0, 1 or 2; and q is 1 or 2 but both p and q cannot be 2, or 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is optionally substituted alkene, alkyne, or any 2 adjacent carbon atoms of a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;
R8 is alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R13;
R9, R10, R11 and R12 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, or hydroxy, alkoxy, amino, NR14R15, thio or alkylthio, provided that only one hydroxy, alkoxy, amino, NR14R15, thio or alkylthio group is bonded to any one carbon atom; 
where Z is O, NR18 or S;
R16 and R17 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy, alkyloxycarbonyl, amino, NR19R20, carbamoyl, ureido, thio or alkylthio;
R14, R15, R18, R19 and R20 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
R1 and R2 are each independently hydrogen, fluorine or alkyl;
R3 is aryl or heteroaryl;
R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or
CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or
COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or
SO2-cycloalkyl, SO2-aryl, SO2-alkyl-cycloalkyl, SO2-alkyl-aryl, SO2-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl; or
C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCN)NH-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocycloalkyl; or
C(NNO2)NH-alkyl, C(NNO2)NH-cycloalkyl, C(NNO2)NH-aryl, C(NNO2)NH-alkyl-cycloalkyl, C(NNO2)NH-alkyl-aryl, C(NNO2)NH-heteroaryl, C(NNO2)NH-alkyl-heteroaryl, C(NNO2)NH-heterocycloalkyl, C(NNO2)NH-alkyl-heterocycloalkyl; or
C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or
C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocycloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or
C(NOR21)NH-alkyl, C(NOR21)NH-cycloalkyl, C(NOR21)NH-aryl, C(NOR21)NH-alkyl-cycloalkyl, C(NOR21)NH-alkyl-aryl, C(NOR21)NH-heteroaryl, C(NOR21)NH-alkyl-heteroaryl, C(NOR21)NH-heterocycloalkyl, C(NOR21)NH-alkyl-heterocycloalkyl;
R5 is hydrogen or alkyl;
R21 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
m is an integer of 0 to 2; and
n is an integer of 1 to 3.
Advantageously, it has been found that the compounds of formulas I and II are useful for preventing or treating alopecia induced by chemotherapy or radiotherapy (radiation treatment).
The present invention provides methods for preventing and treating alopecia induced by chemotherapy or radiotherapy by administering to a mammalian specie, preferably a human, in need thereof a therapeutically effective amount of a compound of formula I or II.
The formula I compounds and methods for their preparation are described in WO 99/65884 and the formula II compounds and methods for their preparation are described in WO 99/24416, both of which are incorporated herein by reference thereto. Alternatively, compounds of formula II can be prepared by the processes discussed below.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
As used herein, the phrase xe2x80x9ccompounds of the inventionxe2x80x9d means, collectively, compounds falling within formulas I and II and pharmaceutically-acceptable salts, solvates, and hydrates thereof. Methods of salt formation, solvation, and hydrate formation are well known in the art. The invention also encompasses mixtures of stereoisomers of compounds of the invention. Stereoisomers include, but are not limited to, enantiomers, diastereomers, and racemates where the compound has one or more chiral centers. All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. All configurational isomers of compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention very particularly embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cycloalkyl or heterocycloalkyl rings.
In addition, salts of compounds of formulas I and II that are pharmaceutically unsuitable but useful in other respects, for example, for the isolation or purification of compounds of formulas I or II, are also encompassed by the invention.
The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound""s identity.
The phrase xe2x80x9cpharmaceutically-acceptable salt(s),xe2x80x9d as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds of the invention. Examples of such pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts and mixtures thereof. Also included are salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, benzoates, ascorbates, salicylates, and the like. In addition, pharmaceutically acceptable salts of compounds of formula I can be formed with alkali metals, such as sodium, potassium and lithium; alkaline earth metals, such as calcium and magnesium; organic bases, such as dicyclohexylarnine, tributylamine, and pyridines, and the like; and amino acids, such as arginine, lysine, and the like.
Salts of compounds of the invention encompass solvates, racemates, and all stereoisomeric forms thereof, including enantiomers and diastereomers (for example, D-tartrate and L-tartrate salts).
As used herein, the term xe2x80x9csolvatexe2x80x9d means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. When the solvent is water the solvate is termed a xe2x80x9chydratexe2x80x9d.
It should be noted that any heteroatom with unsatisfied valances is assumed to have the hydrogen atoms necessary to satisfy the valances.
Carboxylate anion refers to a negatively charged group xe2x80x94COOxe2x88x92.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituent groups, R22 as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with xe2x80x9cbranched alkyl groupxe2x80x9d. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary R22 substituents may include, but are not limited to, one or more of the following groups: halo (such as F, Cl, Br or I), haloalkyl (such as CCl3 or CF3), alkoxy, alkylthio, hydroxy, carboxy (xe2x80x94COOH), alkyloxycarbonyl, alkylcarbonyloxy, amino (xe2x80x94NH2), carbamoyl, urea, amidinyl or thiol (xe2x80x94SH). Alkyl groups as defined may also comprise one or more carbon to carbon double bonds or one or more carbon to carbon triple bonds.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon double bond.
The term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio.
The terms xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkylthioxe2x80x9d, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (xe2x80x94Oxe2x80x94) or a sulfur linkage (xe2x80x94Sxe2x80x94), respectively.
Sulfoxide and sulfone denote groups bonded by xe2x80x94SOxe2x80x94 and xe2x80x94SO2xe2x80x94 linkages respectively.
The term xe2x80x9calkoxycarbonylxe2x80x9d, as used herein, denotes an alkoxy group bonded through a carbonyl group.
The term xe2x80x9calkylcarbonylxe2x80x9d refers to an alkyl group bonded through a carbonyl group.
The term xe2x80x9calkylcarbonyloxyxe2x80x9d, as used herein, denotes an alkycarbonyl group that is bonded through an oxygen linkage.
The term xe2x80x9carylalkylxe2x80x9d, as used herein, denotes an aromatic ring bonded to an alkyl group as described above.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O)t (t=0, 1 or 2) or thiol.
The term xe2x80x9cheteroarylxe2x80x9d refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include the folowing: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, tetrazolyl, pynrdazinyl, pyrimidinyl, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl and tetrahydropyranyl. Exemplary substituents include one or more of the following: halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O)t (t=0, 1 or 2) or thiol.
The term xe2x80x9cheteroaryliumxe2x80x9d refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms.
The term xe2x80x9cquaternary nitrogenxe2x80x9d refers to a tetravalent positively charged nitrogen atom including, e.g., the possitively charged nitrogen in a tetraalkylammonium group (e.g., tetramethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g., trimethylhydroammonium, N-hydropyridinium), the positively charged nitrogen in amine N-oxides (e.g., N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).
The term xe2x80x9cheteroatomxe2x80x9d means O, S or N, selected on an independent basis.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, fluorine or iodine.
Preferred formula I compounds are those wherein
R is R6, COR7 or CONR6R7;
R6 is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
R7 is H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0, 1 or 2; and q is 1 or 2, or 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is optionally substituted alkene, alkyne, or any two adjacent carbon atoms of a cycloalkyl ring;
R8 is alkyl with two or more carbon atoms, aryl, heteroaryl or R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O; and
R16 and R17 are each independently H, alkyl or cycloalkyl.
More preferred formula I compounds are those wherein
R is COR7;
R7 is H, alkyl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0 or 1; and q is 1, or 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is an optionally substituted alkene;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O; and
R16 and R17 are each independently H, alkyl or cycloalkyl.
A second group of more preferred compounds of formula I are those wherein
R is COR7;
R7 is alkyl, arylalkyl, heteroaryl or heteroarylalkyl; 
where p is 0 or 1; and q is 1;
R9, R10, R11 and R12 are each independently H or alkyl;
R8 is R13; 
where Z is O;
R16 is alkyl or cycloalkyl; and
R17 is H.
A third group of more preferred compounds of formula I are those wherein
R is COR7;
R7 is alkyl, arylalkyl, heteroaryl or heteroarylalkyl; 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is an optionally substituted alkene or alkyne;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O;
R16 is alkyl or cycloalkyl; and
R17 is H.
A fourth group of more preferred compounds of formula I are those wherein
R is R6;
R6 is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0 or 1; and q is 1,or 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is an optionally substituted alkene;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O; and
R16 and R17 are each independently H, alkyl or cycloalkyl.
A fifth group of more preferred formula I compounds are those wherein
R is R6;
R6 is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0 or 1; and q is 1;
R9, R10, R11 and R12 are each independently H or alkyl;
R8 is R13; 
where Z is O;
R16 is alkyl or cycloalkyl; and
R17 is H.
A sixth group of more preferred compounds of formula I are those wherein
R is R6;
R6 is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is an optionally substituted alkene or alkyne;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O;
R16 is alkyl or cycloalkyl; and
R17 is H.
A seventh group of more preferred formula I compounds are those wherein
R is CONR6R7;
R6 is alkyl, heteroaryl, arylalkyl or heteroarylalkyl;
R7 is H, alkyl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0 or 1; and q is 1, or 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is an optionally substituted alkene;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O; and
R16 and R17 are each independently H, alkyl or cycloalkyl.
An eighth group of more preferred compounds of formula I are those wherein
R is CONR6R7;
R6 is alkyl, arylalkyl, heteroaryl or heteroarylalkyl;
R7 is H, alkyl, heteroaryl, arylalkyl or heteroarylalkyl; 
where p is 0 or 1; and q is 1;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O;
R16 is alkyl or cycloalkyl; and
R17 is H.
A ninth group of more preferred compounds of formnula I are those wherein
R is CONR6R7;
R6 is alkyl, arylalkyl, heteroaryl or heteroarylalkyl;
R7 is H, alkyl, heteroaryl, arylky or hetroarylalkyl; 
where i and j are each independently 0 or 1 but cannot both be 1, and Y is an optionally substituted alkene or alkyne;
R8 is R13;
R9, R10, R11 and R12 are each independently H or alkyl; 
where Z is O;
R16 is alkyl or cycloalkyl; and
R17 is H.
Preferred compounds of formula II (designated herein as Group IIa) are those wherein
R1 and R2 are each independently hydrogen or alkyl; 
where L is oxygen, sulfur or NR25;
R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or
CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or
COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or
SO2-cycloalkyl, SO2-aryl, SO2-alkyl-cycloalkyl, SO2-alkyl-aryl, SO2-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl; or
C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCN)NH-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocycloalkyl; or
C(NNO2)NH-alkyl, C(NNO2)NH-cycloalkyl, C(NNO2)NH-aryl, C(NNO2)NH-alkyl-cycloalkyl, C(NNO2)NH-alkyl-aryl, C(NNO2)NH-heteroaryl, C(NNO2)NH-alkyl-heteroaryl, C(NNO2)NH-heterocycloalkyl, C(NNO2)NH-alkyl-heterocycloalkyl; or
C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or
C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocycloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or
C(NOR21)NH-alkyl, C(NOR21)NH-cycloalkyl, C(NOR21)NH-aryl, C(NOR21)NH-alkyl-cycloalkyl, C(NOR21)NH-alkyl-aryl, C(NOR21)NH-heteroaryl, C(NOR21)NH-alkyl-heteroaryl, C(NOR21)NH-heterocycloalkyl, C(NOR21)NH-alkyl-heterocycloalkyl;
R5 is hydrogen or alkyl;
R21 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R23 and R24 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R25 is hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
m is an integer of 0 to 2; and
n is an integer of 1 to 3.
More preferred compounds of formula II (designated herein as Group IIb) are those wherein
R1 and R2 are each independently hydrogen or alkyl; 
where L is oxygen;
R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or
CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or
COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or
SO2-cycloalkyl, SO2-aryl, SO2-alkyl-cycloalkyl, SO2-alkyl-aryl, SO2-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl; or
C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCN)NH-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocycloalkyl; or
C(NNO2)NH-alkyl, C(NNO2)NH-cycloalkyl, C(NNO2)NH-aryl, C(NNO2)NH-alkyl-cycloalkyl, C(NNO2)NH-alkyl-aryl, C(NNO2)NH-heteroaryl, C(NNO2)NH-alkyl-heteroaryl, C(NNO2)NH-heterocycloalkyl, C(NNO2)NH-alkyl-heterocycloalkyl; or
C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or
C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocycloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or
C(NOR21)NH-alkyl, C(NOR21)NH-cycloalkyl, C(NOR21)NH-aryl, C(NOR21)NH-alkyl-cycloalkyl, C(NOR21)NH-alkyl-aryl, C(NOR21)NH-heteroaryl, C(NOR21)NH-alkyl-heteroaryl, C(NOR21)NH-heterocycloalkyl, C(NOR21)NH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R21 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R23 and R24 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
m is an integer of 0 to 2; and
n is an integer of 1 to 3.
A second group of more preferred formula II compounds (designated herein as Group IIc) are those wherein
R1 and R2 are each independently hydrogen or alkyl; 
where L is sulfur;
R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or
CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or
COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or
SO2-cycloalkyl, SO2-aryl, SO2-alkyl-cycloalkyl, SO2-alkyl-aryl, SO2-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl; or
C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCN)NH-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocycloalkyl; or
C(NNO2)NH-alkyl, C(NNO2)NH-cycloalkyl, C(NNO2)NH-aryl, C(NNO2)NH-alkyl-cycloalkyl, C(NNO2)NH-alkyl-aryl, C(NNO2)NH-heteroaryl, C(NNO2)NH-alkyl-heteroaryl, C(NNO2)NH-heterocycloalkyl, C(NNO2)NH-alkyl-heterocycloalkyl; or
C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or
C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocycloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or
C(NOR21)NH-alkyl, C(NOR21)NH-cycloalkyl, C(NOR21)NH-aryl, C(NOR21)NH-alkyl-cycloalkyl, C(NOR21)NH-alkyl-aryl, C(NOR21)NH-heteroaryl, C(NOR21)NH-alkyl-heteroaryl, C(NOR21)NH-heterocycloalkyl, C(NOR21)NH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R21 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R23 and R24 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
m is an integer of 0 to 2; and
n is an integer of 1 to 3.
A third group of more preferred compounds of formula II (designated herein as Group IId) are those wherein
R1 and R2 are each independently hydrogen or alkyl; 
where L is NR25;
R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or
CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or
COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or
SO2-cycloalkyl, SO2-aryl, SO2-alkyl-cycloalkyl, SO2-alkyl-aryl, SO2-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl; or
C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCN)NH-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocycloalkyl; or
C(NNO2)NH-alkyl, C(NNO2)NH-cycloalkyl, C(NNO2)NH-aryl, C(NNO2)NH-alkyl-cycloalkyl, C(NNO2)NH-alkyl-aryl, C(NNO2)NH-heteroaryl, C(NNO2)NH-alkyl-heteroaryl, C(NNO2)NH-heterocycloalkyl, C(NNO2)NH-alkyl-heterocycloalkyl; or
C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or
C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocycloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or
C(NOR21)NH-alkyl, C(NOR21)NH-cycloalkyl, C(NOR21)NH-aryl, C(NOR21)NH-alkyl-cycloalkyl, C(NOR21)NH-alkyl-aryl, C(NOR21)NH-heteroaryl, C(NOR21)NH-alkyl-heteroaryl, C(NOR21)NH-heterocycloalkyl, C(NOR21)NH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R21 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R23 and R24 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R25 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
m is an integer of 0 to 2; and
n is an integer of 1 to 3.
A fourth group of more preferred formula II compounds (designated herein as Group IIe) are those wherein
R1 and R2 are each independently hydrogen or alkyl; 
where L is oxygen;
R4 is aryl, heteroaryl, CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R23 and R24 are hydrogen;
m is the integer 0; and
n is the integer 1.
A fifth group of more preferred formula II compounds (designated herein as Group IIf) are those wherein
R1 and R2 are independently hydrogen or alkyl; 
where L is oxygen;
R4 is aryl, heteroaryl, CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R23 is alkyl;
R24 is hydrogen;
m is the integer 0; and
n is the integer 1.
A sixth group of more preferred formula II compounds (designated herein as Group IIg) are those wherein
R1 and R2 are independently hydrogen or alkyl; 
where L is sulfur;
R4 is aryl, heteroaryl, CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R23 is alkyl;
R24 is hydrogen;
m is the integer 0; and
n is the integer 1.
A seventh group of more preferred compounds of formula II (designated herein as Group IIh) are those wherein
R1 and R2 are independently hydrogen or alkyl; 
where L is NR25;
R4 is aryl, heteroaryl, CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R23 is alkyl;
R24 is hydrogen;
R25 is hydrogen, alkyl, cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycloalkyl or alkyl-heterocycloalkyl;
m is the integer 0; and
n is the integer 1.
An eighth group of more preferred compounds of formula II (designated herein as Group IIi) are those wherein
R1 and R2 are independently hydrogen or alkyl; 
where L is NR25;
R4 is aryl, heteroaryl, CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
R5 is hydrogen;
R23 is hydrogen;
R24 is alkyl;
R25 is hydrogen;
m is the integer 0; and
n is the integer 1.
An ninth group of more preferred compounds of formula II (designated herein as Group IIj) are compounds of the formula: 
or enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, and R5 are independently hydrogen or alkyl;
R23 is alkyl, aryl, or heteroaryl;
R24 is hydrogen, alkyl, aryl, or heteroaryl;
R26 and R27 are independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy, or alkoxy;
R28 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, CONR29R30, COR31, or COOR32;
R29, R30, R31 and R32 are independently hydrogen, alkyl, or aryl;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 5.
A tenth group of more preferred compounds of formula II (designated herein as Group IIk) are compounds of the formula: 
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof, wherein R33 is hydrogen, alkyl, or cycloalkyl.
An eleventh group of more preferred compounds of formula II (designated herein as Group IIl) are compounds of the formula: 
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof, wherein R33 is hydrogen, alkyl, or cycloalkyl.
A twelfth group of more preferred compounds of formula II (designated herein as Group IIm) are compounds of the formula: 
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof, wherein:
R34 is alkyl;
R35 is hydrogen or alkyl;
X is NR36 or CHNR36R37;
R36 and R37 are independently hydrogen, alkyl, or cycloalkyl; and
t is 0, 1, 2 or 3.
A thirteenth group of more preferred compounds of formula II (designated herein as Group IIn) are compounds of the formula: 
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof, wherein R36 and R37 are independently hydrogen, alkyl, or cycloalkyl.
In another embodiment, compounds of formula II include, but are not limited to, those listed in Table 1 below and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
Preferred salts of the above compounds are the hydrochloride, the hydrobromide, the dihydrochloride, the sulfate, the trifluoroacetate, the tartrate, the fumarate, the succinate, the maleate, the citrate, the methanesulfonate, the bromate, and the iodate salts or mixtures thereof.
In addition to the methods described in WO 99/24416 and WO 99/65884, certain compounds of the invention, such as those of formula IIj, can be prepared as described in Scheme 1 below. Thus, in another embodiment, the present invention relates to processes for the synthesis of compounds of the formula IIj: 
wherein:
R1, R2, and R5 are independently hydrogen or alkyl;
R23 is alkyl, aryl, or heteroaryl;
R24 is hydrogen, alkyl, aryl, or heteroaryl;
R26 and R27 are independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy, or alkoxy;
R28 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, CONR29R30, COR31, or COOR32;
R29, R30, R31 and R32 are independently hydrogen, alkyl, or aryl;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 5.
This method is preferred for the synthesis of compounds of the formula IIj but can be adapted by those of skill in the art for the synthesis of other compounds of the invention. The synthetic reactions of this embodiment are outlined below in Scheme 1, where the following terms apply:
L is a suitable leaving group, such as halogen or sulfonate (R25SO2Oxe2x88x92, CF3SO2Oxe2x88x92, etc., wherein R25 is alkyl, cycloalkyl, or aryl);
M is hydrogen, Li, Na, K, Cs, or a quaternary ammonium ion, e.g., (R25)4N or quaternary ammonium ions comprising cyclic alkenetetramines, such as hexamethylenetetramine;
X is hydroxy, halogen or acyloxy (R25COOxe2x88x92, R25OCOOxe2x88x92, etc.);
Y is O, S, NH, N-alkyl, N-aryl or N-acyl;
Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH2, N-alkyl, N-aryl or N-acyl; and
P is a nitrogen-protecting group (Boc, Cbz, R3Si, etc.). When a functional group is termed xe2x80x9cprotected,xe2x80x9d this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds involved in the present processes will be recognized from the specification taking into account the level of skill in the art, and with reference to standard textbooks such as Greene, T. W., Protective Groups in Organic Synthesis, 3rd edition (1999), incorporated herein by reference.
The processes generally involve reaction of xcex1-halo ketones 2 (commercially available or readily synthesized by well-known methods) with an azide to give xcex1-azido ketones 3. Reduction of 3 with a reducing reagent gives xcex1-amino ketones 4.
Alternatively and more advantageously, the xcex1-amino ketones 4 are prepared by reaction of xcex1-halo ketones 2 with a cyclic alkylenetetramine such as hexamethylenetetramine and the like, followed by hydrolysis of the resulting, new quaternary ammonium salt 3xe2x80x2. This reaction provides excellent yields of the desired intermediate compound 4, above 90%.
Thereafter, reacting the xcex1-amino ketones 4 with an xcex1-halo acyl halide 5 in the presence of a base or, alternatively, coupling the xcex1-amino ketones 4 with an xcex1-halo acid, produces the corresponding amides 6. Then, ring closure of 6 with a dehydrating reagent affords 2-oxazolylalkyl halides 7. When a conventional dehydrating reagent, such as trihalophosphorus oxide like POCl3 is used, product isolation is difficult due to the formation of large amounts of hydrochloric and phosphoric acids. Thus, the process of the present invention preferably utilizes the Burgess"" reagent which produces excellent yields and permits easy, safe product isolation from water.
Subsequent treatment of 2-oxazolylalkyl halides 7 with sulfur-containing reagent 8 or 8xe2x80x2 affords new key intermediate compounds, 2-oxazolylalkyl sulfides 9. Coupling of 9 with 5-halo-2-aminothiazole 10 gives 5-(2-oxazolylalkylthio)-2-aminothiazoles 11. Coupling of 11 with an azacycloalkanoic acid derivative 12 affords thiazolyl amides 13, which may be deprotected (in the case where P is a protecting group, e.g., Boc) to give 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles II.
While specifically described for synthesis of compounds of formula IIj, the synthetic methods outlined in Scheme 1, or appropriate steps thereof, can be adapted or used directly by one of skill in the art for the synthesis of other compounds of general formulas I and II. 
As set forth in Scheme 1, the processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs involve the following transformations:
Step (a) involves reacting an a-substituted ketone 2 such as, for example, an xcex1-halo ketone, with an azide in a suitable solvent or solvent mixtures to give an xcex1-azido ketone 3; or, more desirably, (axe2x80x2) reacting an a-substituted ketone 2 like the xcex1-halo ketone with a cyclic alkylenetetramine such as, for example, hexamethylenetetramine in a suitable solvent or solvent mixtures to give a new quaternary ammonium salt 3xe2x80x2.
The xcex1-halo ketone includes xcex1-halo aliphatic and xcex1-halo aromatic ketones. The preferred xcex1-halo ketones are xcex1-halo pinacolones with xcex1-bromo pinacolone most preferred. A sulfonate, for example, RSO2Oxe2x80x94 (where R is alkyl, aryl or heteroaryl), CF3SO2Oxe2x80x94 and the like, may be substituted for the halogen in the xcex1-position. The azides include both metal azides and quaternary ammonium azides. The metal azides are preferred with sodium azide most preferred. Suitable solvent(s) include solvents such as hydrocarbons, ethers, amides, for example, dimethylformamide, ketones, etc., or mixtures thereof, with ketones such as acetone preferred for both reactions (a) and (axe2x80x2).
Step (b) comprises reacting the xcex1-azido ketone 3 obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give an xcex1-amino ketone 4, or, more desirably, (bxe2x80x2) reacting the quaternary ammonium salt 3xe2x80x2 obtained in step (axe2x80x2) with an acid in a suitable solvent or solvent mixtures to give an xcex1-amino ketone 4.
The reducing reagent in reaction (b) includes hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl or triarylphosphines like triphenylphosphine. Hydrogen in the presence of a transition metal catalyst is preferred with hydrogen and palladium over activated carbon most preferred. Suitable solvent(s) in reaction (b) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as methanol preferred. Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as, for example, hydrochloric acid in ethanol to give xcex1-amino ketone acid salt which can be isolated as the acid salt or free amine forms.
The acid in reaction (bxe2x80x2) includes, but is not limited to, protic acids such as HCl, HBr, HI, H2SO4, H3PO4, etc., with HCl preferred. Suitable solvent(s) in reaction (bxe2x80x2) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as ethanol preferred. The xcex1-amino ketone product may be isolated as the salt or free base forms.
Step (c) involves reacting (acylating) the xcex1-amino ketone 4 or its acid salt obtained in step (b) or (bxe2x80x2) with an a-substituted acyl derivative 5 such as, for example, an xcex1-halo acyl halide, in the presence of a base and in a suitable solvent or solvent mixtures to give an amide 6.
The xcex1-halo acyl halide 5 includes xcex1-alkyl or aryl substituted or unsubstituted xcex1-halo acyl halide with the latter preferred. The most preferred xcex1-halo acyl halide is xcex1-chloroacetyl chloride. The base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines with the latter preferred. The most preferred base is triethylamine. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred. Alternatively, the reaction can be carried out using an xcex1-substituted acid instead of the xcex1-substituted acyl derivative and then employing a coupling reagent such as a water-soluble diimide like carbodiimide, haloformate, thionyl halide, etc. In either reaction, a sulfonate, for example, RSO2Oxe2x80x94 (where R is an alkyl, aryl or heteroaryl), CF3SO2Oxe2x80x94 and the like, may be substituted for the halogen in the xcex1-position of the xcex1-halo acyl halide or the xcex1-halo acid reactants which are illustrated.
Step (d) concerns reacting the amide 6 obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative 7 such as, for example, the 2-oxazolylalkyl halide.
Advantageously, the reaction is carried out using (methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess"" reagent) as the dehydrating reagent. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess"" reagent in tetrahydrofuran. Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acid anhydrides and the like, such as, e.g., concentrated sulfuric acid, polyphosphoric acid, etc. Although less conveniently, the dehydrating reagent, for instance, can be trihalophosphorus oxide such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like toluene.
Step (e) is directed to reacting the 2-oxazolylalkyl derivative 7 obtained in step (d) with a sulfur-containing reagent 8 or 8xe2x80x2 in a suitable solvent or solvent mixtures to give 2-oxazolylalkyl sulfide 9, a new key intermediate compound.
The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or its salt, xanthic acids or salts such as ethylxanthic acid potassium salt. Unsubstituted thiourea is preferred. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohol such as methanol or ethanol preferred.
Step (f) concerns reacting the 2-oxazolylalkyl sulfide 9 obtained in step (e) with a 5-halo-2-aminothiazole 10 in the presence of a base and in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-aminothiazole 11.
The 5-halo-2-aminothiazole includes 4-N-substituted or unsubstituted 5-halo-2-aminothiazoles with 5-bromo-2-aminothiazole preferred. A suitable base includes, but is not limited to, metal hydroxide, metal alkoxides, metal carbonates and aqueous amines such as ammonium hydroxide. Sodium hydroxide is preferred. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
Step (g) involves reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole 11 obtained in step (f) with an azacycloalkanoic acid derivative 12 in the presence of a coupling reagent in a suitable solvent or solvent mixtures to give thiazolyl amide 13.
The azacycloalkanoic acid derivative includes N-protected derivatives, for example, N-protected isonipecotic acid or N-protected nip ecotic acid. The preferred nitrogen-protecting groups are Boc, Cbz, silicon derivatives and the like with Boc being the most preferred. The coupling reagent includes, but is not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
Step (h) is directed to reacting the thiazolyl amide 13 obtained in step (g) with a deprotecting reagent in a suitable solvent or solvent mixtures to give a desired 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole II (where R27 is hydrogen).
The choice of the deprotecting reagent is based on the nature of the protecting group (P). For the Boc protecting group, the preferred deprotecting reagent is an acid such as hydrochloric acid or trifluoroacetic acid and suitable solvent(s) for such deprotecting reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
The starting compounds of Scheme 1 are commercially available or may be prepared by methods known to one of ordinary skill in the art.
To further illustrate Scheme 1, a process to make 5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazoles and analogs thereof, for example, starts with reaction of xcex1-bromo pinacolone 2 (R23=Bu-t, R24=H, L=Br) with sodium azide to give an xcex1-azido pinacolone 3 (R23=Bu-t, R24=H). Reduction of xcex1-azido pinacolone 3 (R23=Bu-t, R24=H) with a reducing reagent gives xcex1-amino pinacolone 4 (R23=Bu-t, R24=H). Alternatively and more desirably, the xcex1-amino pinacolone 4 (R23=Bu-t, R24=H) is prepared by reaction of xcex1-bromo pinacolone 2 (R23=Bu-t, R24=H, L=Br) with hexamethylenetetramine followed by hydrolysis of the resulting quaternary ammonium salt 3xe2x80x2(R23=Bu-t, R24=H, L=Br). Coupling of xcex1-amino pinacolone 4 (R23=Bu-t, R24=H) with an xcex1-chloroacetyl chloride 5 (R2=R1=H, L=X=Cl) produces amide 6 (R23=Bu-t, R24=R2=R1=H, L=Cl). Ring closure of 6 with a dehydrating reagent affords 5-t-butyl-2-oxazolylmethyl chloride 7 (R23=Bu-t, R24=R2=R1=H, L=Cl). Treatment of 7 with sulfur-containing reagent 8 or 8xe2x80x2 such as thiourea affords 5-t-butyl-2-oxazolylalkyl sulfide 9 (R23=Bu-t, R24=R2=R1=H, Y=NH, Z=NH2). Coupling of 9 with 5-bromo-2-aminothiazole 10 (R5=H, L=Br) gives 5-(5-t-butyl-2-oxazolylmethylthio)-2-aminothiazole 11 (R23=Bu-t, R24=R2=R1=R5=H). Coupling of 11 with N-Boc azacycloalkanoic acid 12 (X=OH, R26=R27=H, r=0, s=2, P=Boc), affords thiazolyl amide 13 (R23=Bu-t, R24=R2=R1=R5=R26=R27=H, r=0, s=2, P=Boc), which after deprotection, gives rise to the desired 5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazole II (R23=Bu-t, R24=R2=R1=R5=R26=R27=R28=H, r=0, s=2).
The present invention provides a method for preventing or treating chemotherapy-induced alopecia in a mammal, prior to, during, or after undergoing chemotherapy by administering to the mammal with a therapeutically effective amount of a compound of formula I or II. The present invention also provides a method for preventing or treating radiotherapy-induced alopecia in a mammal prior to, during, or after undergoing radiotherapy by administering to the mammal with a therapeutically effective amount of a compound of formula I or II. The therapeutically effective amount of the formula I or II compound is that amount sufficient to prevent or reduce the hair loss that normally accompanies chemotherapy or radiotherapy treatments.
The compounds of this invention may be administered in topical, oral, nasal, ophthalmic, otic, rectal, intravenous, intraperitoneal, intraarticular, subcutaneous, intramuscular, inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts. In a preferred embodiment of the present invention, the compounds are topically administered to the skin, preferably the scalp of a patient.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the amount of chemotherapeutic agent(s) or radiotherapy administered or planned to be administered to the patient; the route of administration; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the chemotherapy or radiotherapy-induced alopecia.
Topical application is the preferred administration route. Topical application may be once or more than once per day depending upon the usual medical considerations. Topical administration, preferably to the scalp, 1 to 2 times prior to chemotherapy or radiotherapy administration would be preferred to prevent alopecia, additional applications may be administered as needed. The compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily before, during, or after the chemotherapy or radio therapy. The compounds of this invention may be prepared in a range of concentrations for topical use. In general, topical compositions comprise about 0.1 mg to 25 mg of active compound per ml of suitable carrier.
In the methods of the present invention, the compounds of formulas I and II are the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) suitably selected with respect to the intended form of administration, that is, topical creams, lotions, solutions, dispersions, shampoos, ointments, gels, spot-ons, dusts, aerosols and the like; and oral tablets, capsules, elixirs, syrups and the like; and consistent with conventional pharmaceutical practices.
The compounds of this invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholines. Liposomal compositions and methods for their preparation are well known to those skilled in the pharmaceutical arts.
The present invention also relates to pharmaceutical compositions containing a compound of formula I or II in combination with a pharmaceutically acceptable carrier to prevent or treat chemotherapy or radiotherapy-induced alopecia. Topical formulations suitable for use in the methods of the present invention include, but are not limited to, creams, lotions, solutions, dispersions, shampoos, ointments, gels, spot-ons, dusts, impregnated dressings, aerosols, and the like. The topical formulations may contain appropriate conventional additives such as preservatives, solvents, coloring agents, emollients, and the like.
Death of proliferating stem cells in the hair follicles has a dramatic impact on the retention of hair following chemotherapy/radiotherapy treatment. The activity of the compounds of this invention to inhibit stem cell proliferation and protect them from chemotherapy/radiotherapy-induced cell death may be evaluated in a keratinocyte proliferation assay using the following procedure.
Adult female mice are shaved on the dorsal skin beginning on day 1. Hyperplasia is induced by treatment with the phorbol ester TPA (5 xcexcg topically in 0.2 ml acetone) the morning of the next day (day 2), and is called time zero (T-0). At time points relative to that treatment, inhibitors are added to prevent the induced proliferation of keratinocytes. For twice a day dosing, drugs are typically administered 30 minutes after TPA (T-0.5) and again eight hours later (T-8). On day 3, at T-23, mice are injected with BrdU (4.5 mg in 0.3 ml PBS). One hour later (T-24) mice are euthanized, and the skin removed for preparation of keratinocytes.
First, subdermal fat is removed by scraping with a scalpel, the skin is washed with DPBS, and allowed to dry for xcx9c10 minutes in a cell culture dish. Keratinocytes are liberated from the tissue by the addition of 10 ml of 0.25% trypsin/EDTA, and tissue maceration with scissors. Subsequent incubation at 37xc2x0 C. in 5% CO2 for 2-3 hours completes the dissociation of cells from the dermis.
Digested skin tissue is pipetted through a Falcon 2350 cell strainer into centrifuge tubes. Recovery of keratinocytes is enriched by rinsing the cell strainer with 10 ml keratinocyte media (KM: S-MEM/10% dialyzed FBS supplemented with Insulin, EGF, Transferrin, phosphoethanolamine, ethanolamine, hydrocortisone, and glutamine). The cells are concentrated by centrifugation and resuspended in 10 ml fresh KM.
Basal keratinocytes are separated from other cell types by centrifugation through a gradient by layering the suspended cell pellet on top of 20 ml of 45% Percoll (w/1.5 mM NaCl) and centrifugation at 1000 RPM in a refrigerated clinical centrifuge (4xc2x0 C.). The cell pellet is resuspended in 80% EtOH, and placed at xe2x88x9220xc2x0 C. overnight.
The next day, about 2 million cells are removed from the ethanol solution and prepared for flow cytometry analysis by centrifugation and resuspension in 1 ml of 2N HCl (in 0.5% Triton X-100). The cells are incubated in this solution for 30 minutes, with intermittent mixing. The cells are removed from this solution by centrifugation, and washed with 1.0 ml of 0.1M sodium tetraborate (pH 8.5), pelleted again, and resuspended in 1.0 ml 0.5% Tween 20 in 1% BSA. Conditioned cells are then pelleted and resuspended in 20 xcexcl of antiBrdU antibody and incubated for 30 min. at room temperature. This immunoreaction is stopped by addition of 500 xcexcl Tween20/BSA/BS solution, mixing and pelleting of the cells by centrifugation. Cells are counterstained by resuspending the cell pellet in 1.0 ml of 0.1 xcexcM Topro-3 dye solution (100 xcexcl of 10 mg/ml Rnase stock added to 10 ml PBS, plus 1 xcexcl Topro-3 dye). Incubate 15 minutes. BrdU incorporation is scored by flow cytometry and a proliferative index is calculated. Test compounds which show a low proliferation index in this assay, as compared to high levels of proliferation induced by TPA alone, are predicted to protect hair follicles from chemotherapy/radiotherapy-induced alopecia.